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Head and Neck Cancers

Head and neck cancers are malignancies arising in the upper aerodigestive tract (this includes: lip, tongue, salivary glands, mouth, oropharynx, nasopharynx, hypopharynx, nasal cavity, and larynx). Laryngeal (voice-box) cancer is the most frequent type, accounting for about a quarter of head and neck cancers.

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Laryngeal Cancer
Hypopharyngeal Cancer
Nasopharyngeal Cancer
Oropharyngeal Cancer
Oral Cancer
Salivary Gland Cancer
Tracheal (windpipe) Cancer
Molecular Biology of Head and Neck Cancers
Head and Neck Cacer Resources
Latest Research Publications

Head and Neck Cacer Resources (16 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Kim SH, Kang JG, Kim CS, et al.
Doxorubicin has a synergistic cytotoxicity with cucurbitacin B in anaplastic thyroid carcinoma cells.
Tumour Biol. 2017; 39(2):1010428317692252 [PubMed] Related Publications
In this study, the combined effect of doxorubicin with cucurbitacin B on survival of anaplastic thyroid carcinoma cells was evaluated. For experiments, 8505C and CAL62 human anaplastic thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, and cytotoxic activity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, multiplexed cytotoxicity assay, and cytotoxicity assay, respectively. Reactive oxygen species production was measured. In experiments, doxorubicin and cucurbitacin B reduced cell viability in a dose- and time-dependent manner. Cotreatment of doxorubicin and cucurbitacin B, compared with treatment of doxorubicin alone, decreased the percentage of viable cells and increased cytotoxic activity. All of the combination index values were lower than 1.0, suggesting the synergism between doxorubicin and cucurbitacin B in induction of cytotoxicity. In cells treated with both doxorubicin and cucurbitacin B, compared with doxorubicin alone, the protein levels of cleaved poly(adenosine diphosphate-ribose) polymerase and cyclooxygenase 2 and reactive oxygen species production were enhanced. In contrast, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma 2 and survivin and B-cell chronic lymphocytic leukemia/lymphoma 2/B-cell chronic lymphocytic leukemia/lymphoma 2-associated x protein ratio were diminished. The protein levels of Janus kinase 2 and signal transducer and activator of transcription 3 were reduced, while phospho-extracellular signal-regulated kinase 1/2 protein levels were elevated without change in total extracellular signal-regulated kinase 1/2 protein levels. These results suggest that doxorubicin synergizes with cucurbitacin B in induction of cytotoxicity in anaplastic thyroid carcinoma cells. Moreover, synergistic cytotoxicity of doxorubicin with cucurbitacin B is mediated by B-cell chronic lymphocytic leukemia/lymphoma 2 family proteins, survivin, and reactive oxygen species and modulated by Janus kinase 2/signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 in anaplastic thyroid carcinoma cells.

Abu-Farsakh S, Wu T, Lalonde A, et al.
High expression of Claudin-2 in esophageal carcinoma and precancerous lesions is significantly associated with the bile salt receptors VDR and TGR5.
BMC Gastroenterol. 2017; 17(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression.
METHODS: Claudin-2 expression was examined by immunohistochemistry on tissue microarrays, containing EAC, high grade dysplasia (HGD), low grade dysplasia (LGD), Barrett's esophagus (BE), columnar cell metaplasia (CM), squamous cell carcinoma (SCC), and squamous epithelium (SE) cases. Intensity (0 to 3) and percentage were scored for each case. High expression was defined as 2-3 intensity in ≥ 10% of cells.
RESULTS: Claudin-2 was highly expressed in 77% EAC (86/111), 38% HGD (5/13), 61% LGD (17/28), 46% BE (18/39), 45% CM (29/65), 88% SCC (23/26), and 14% SE (11/76). It was significantly more highly-expressed in EAC, SCC and glandular lesions than in SE and more in EAC than in BE and CM. A significant association was found between Claudin-2 expression and VDR and TGR5 expression. No significant association was found between expression of Claudin-2 and age, gender, grade, stage, or patients' survival time in EAC and SCC.
CONCLUSIONS: We conclude that Claudin-2 expression is significantly associated with bile acid receptors VDR and TGR5 expression. Our studies identify a novel role of a tight junction protein in the development and progression of esophageal mucosal metaplasia, dysplasia and carcinoma.

Khan S, Mikhail S, Xiu J, Salem ME
Molecular biology of gastroesophageal cancers: opportunities and challenges.
Clin Adv Hematol Oncol. 2017; 15(1):75-82 [PubMed] Related Publications
Gastroesophageal (GE) malignancies make up a significant and growing segment of newly diagnosed cancers. Approximately 80% of patients who have GE cancers die within 5 years of diagnosis, which means that effective treatments for these malignancies need to be found. Currently, targeted therapies have a minimal role in this disease group. Intensive study of the molecular biology of GE cancers is a relatively new and ongoing venture, but it has already led to a significant increase in our understanding of these malignancies. This understanding, although still limited, has the potential to enhance our ability to develop targeted therapies in conjunction with the ability to identify actionable gene mutations and perform genomic profiling to predict drug resistance. Several cell surface growth factor receptors have been found to play a prominent role in GE cancer cell signaling. This discovery has led to the approval of 2 agents within the last few years: trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody used in the first-line treatment of HER2-positive GE cancers, and ramucirumab, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody that is currently used in later lines of therapy. This review discusses the current state of molecular testing in GE cancers, along with the known molecular biology and current and investigational treatments. The development of trastuzumab and ramucirumab represents a significant advance in our ability to make use of GE tumor molecular profiles. As our understanding of the impact of molecular aberrations on drug effectiveness and disease outcomes increases, we anticipate improved therapy for patients with GE cancers.

Marta GN, Saad ED
Assessment of quality of life in phase III trials of radiotherapy in localized or locally advanced head and neck cancer over the past 17 years.
Ann Palliat Med. 2017; 6(1):73-80 [PubMed] Related Publications
BACKGROUND: We investigated the extent to which health-related quality of life (HRQOL) parameters have been used as endpoints in recent phase III trials on radiotherapy for head and neck cancer, as well as the frequency and correlates of significant HRQOL gains.
METHODS: Using the medical subject headings "head and neck neoplasms" and "radiotherapy", we searched PubMed for the main paper reporting phase III trials published between 1/1999 and 12/2015 in 16 leading journals.
RESULTS: We found 88 trials that fulfilled the selection criteria (32,707 patients/191 trial arms). HRQOL was listed as an endpoint in 21.3% of trials. HRQOL comparisons between groups were reported in only 12 trials, with statistically significant differences between HRQOL parameters in only three studies, two of which favored the experimental arm.
CONCLUSIONS: HRQOL has been infrequently investigated in phase III trials of radiotherapy in head and neck cancer, typically with no significant differences found between groups.

Vuong HG, Kondo T, Pham TQ, et al.
Prognostic significance of diffuse sclerosing variant papillary thyroid carcinoma: a systematic review and meta-analysis.
Eur J Endocrinol. 2017; 176(4):431-439 [PubMed] Related Publications
OBJECTIVE: Diffuse sclerosing variant papillary thyroid carcinoma (DSVPTC) is an uncommon variant of papillary thyroid carcinoma (PTC). The biological behaviors and prognostic outcomes of this variant, however, are still controversial. The aim of this systematic review and meta-analysis is to investigate the prognostic significance and outcomes of DSVPTCs in comparison with classical PTCs (cPTCs).
METHODS: An electronic search was performed in five libraries: PubMed, Scopus, ISI, World Health Organization Global Health Library (WHO GHL) and Virtual Health Library (VHL) in June 2016. Published data were extracted and were pooled into odds ratios (OR), mean differences and corresponding 95% confidence intervals (CI) using random-effect model. Publication bias was analyzed using Egger's regression test and funnel plot observation.
RESULTS: From 315 articles, we included 16 articles comprising 732 DSVPTCs for meta-analysis. Overall, DSVPTC manifested more aggressive clinicopathological behaviors than cPTC such as higher rate of vascular invasion (OR: 5.33; 95% CI: 3.08-9.23), extrathyroidal extension (OR: 2.96; 95% CI: 2.04-4.30), lymph node metastasis (OR: 5.40; 95% CI: 2.82-10.35), distant metastasis (OR: 3.61; 95% CI: 1.89-6.88) and were more likely to relapse (OR: 2.83; 95% CI: 1.59-5.05). DSVPTC patients were associated with a worsened overall survival (HR: 1.89; 95% CI: 1.36-2.62).
CONCLUSION: DSVPTCs should be considered high-risk PTCs because of high propensity for tumor invasion, metastasis, relapse and mortality. Aggressiveness of DSVPTCs might be related to a different molecular pathway than that in cPTCs.

Sakaguchi M, Maebayashi T, Aizawa T, et al.
Clinical Outcomes of Hypopharyngeal Cancer Receiving Definitive Radiotherapy with Concurrent Chemotherapy.
Anticancer Res. 2017; 37(2):941-947 [PubMed] Related Publications
AIM: To evaluate clinical outcomes of concurrent chemoradiotherapy (CCRT) in patients with hypopharyngeal cancer (HPC).
PATIENTS AND METHODS: This retrospective study included 80 patients (75 males) aged 48 to 78 years (median=66 years) with a histological diagnosis of HPC. The 5-fluorouracil and cisplatin (FP) regimen was used until 2007 and then switched to the docetaxel, cisplatin, and 5-fluorouracil (TPF) regimen. Radiotherapy was administered to a total dose of 60 to 72 Gy (median=66 Gy).
RESULTS: The 5-year overall survival and disease-free survival rates were 49.3% and 60.7%, respectively. Improved disease-free survival was associated with lower N-stage (hazard ratio=0.249; 95% confidence interval=0.096-0.643; p=0.041).
CONCLUSION: There were no significant differences in overall and disease-free survival between patients receiving CCRT with the TPF regimen and those who received FP for a long period of treatment but did not finish two courses.

Sasaki K, Uchikado Y, Okumura H, et al.
Role of (18)F-FDG-PET/CT in Esophageal Squamous Cell Carcinoma After Neoadjuvant Chemoradiotherapy.
Anticancer Res. 2017; 37(2):859-864 [PubMed] Related Publications
AIM: The aim of this study was to assess the role of (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT) in predicting pathological response and survival in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT).
PATIENTS AND METHODS: Thirty patients with advanced ESCC received nCRT followed by surgery, and underwent FDG-PET/CT twice before and after nCRT. We compared the results of FDG-PET/CT with the pathological results and prognosis.
RESULTS: Pathological response was found to correlate with the maximum standardised uptake value (SUVmax) after nCRT and the rate of decrease of SUVmax Using univariate analysis, pN, SUVmax after nCRT and the rate of decrease of SUVmax were found to be prognostic factors. Multivariate analysis revealed that only pN was an independent prognostic factor.
CONCLUSION: The prediction of pathological response and prognosis using FDG-PET/CT is not as reliable as pathological detection of lymph node metastasis, but could be a useful method contributing to treatment decisions.

Megwalu UC, Ma Y
Racial Disparities in Oropharyngeal Cancer Stage at Diagnosis.
Anticancer Res. 2017; 37(2):835-839 [PubMed] Related Publications
AIM: To evaluate the impact of race on disease stage at diagnosis in patients with oropharyngeal cancer.
PATIENTS AND METHODS: The cohort included 18,791 adult patients diagnosed with oropharyngeal squamous cell carcinoma between 2004 and 2012, from the Surveillance, Epidemiology, and End Results 18 Database.
RESULTS: After adjusting for age, sex, marital status, tumor site, and year of diagnosis, black race was associated with increased risk of presenting with Stage III or IV disease (OR 1.24, p=0.016), T3 or T4 tumors (OR 2.16, <0.001), distant metastasis (OR 2, p<0.001), and unresectable tumors (OR 1.65, p<0.001). Race was not associated with risk of presenting with nodal metastasis diagnosis (OR 0.93, p=0.241).
CONCLUSION: Black race is associated with increased risk of advanced disease presentation in oropharyngeal cancer.

Hoch S, Thelen K, Vorwerk H, et al.
Impact of Different Treatment Concepts on Regional Failure in Advanced Oropharyngeal Cancer.
Anticancer Res. 2017; 37(2):727-734 [PubMed] Related Publications
BACKGROUND: The management of patients with advanced oropharyngeal cancer is complex and mostly requires a multidisciplinary treatment approach. In general, organ preservation by primary concurrent radiochemotherapy (RCT), or surgery completed by adjuvant radiotherapy are established treatment strategies for these patients. However, it is unclear if primary treatment has an effect on regional tumor control. The purpose of the present study was to evaluate the regional control after different treatment concepts.
PATIENTS AND METHODS: Clinical data, including histological and radiological results, of 82 patients with T2-T3 oropharyngeal cancer and N2 neck were retrospectively analyzed. They underwent either RCT with salvage neck dissection (ND) (n=45), or primary transoral surgery with ND and adjuvant RCT (n=37). In all cases, the primary tumor was successfully treated, without evidence of local failure in the follow-up.
RESULTS: Overall, 11 (13.4%) patients developed regional failure during the follow-up. There were no significant differences in frequency of regional failure (p=0.75), distant metastasis (p=0.35) and overall survival (p=0.22) between treatment groups. However, 5-year disease-free survival was significantly worse (39.0% vs. 57.0%) for patients treated by RCT, with more frequent regional failure detected compared to surgically-treated patients in univariate analysis (p=0.04).
CONCLUSION: Treatment concept does not seem to affect regional tumor control in advanced oropharyngeal cancer after successful treatment of the primary tumor.

Gamez ME, Agarwal M, Hu KS, et al.
Hypofractionated Palliative Radiotherapy with Concurrent Radiosensitizing Chemotherapy for Advanced Head and Neck Cancer Using the "QUAD-SHOT Regimen".
Anticancer Res. 2017; 37(2):685-691 [PubMed] Related Publications
AIM: To analyze the outcomes using the hypofractionated palliative radiotherapy regimen "QUAD-Shot" with concurrent radiosensitizing chemotherapy for advanced head and neck cancer.
MATERIALS AND METHODS: We analyzed twenty-one patients with newly-diagnosed or recurrent head and neck cancer treated with palliative hypofractionated concurrent chemoradiation using the QUAD-Shot regimen.
RESULTS: All patients received at least one cycle of RT, with sixteen patients (76%) completing all three cycles. 85.7 % of patients had objective response to therapy with five patients (23.8%) demonstrating complete response (CR) and thirteen patients (61.9%) demonstrating partial response (PR). Palliation of symptoms was achieved in all (100%) of the sixteen patients that completed the three cycles. Median overall survival and median progression-free survival were 7 and 4 months, respectively.
CONCLUSION: QUAD-Shot palliative radiation therapy coupled with radiosensitizing chemotherapy is efficacious and well-tolerated in patients with newly-diagnosed or recurrent head and neck cancer not amenable to curative therapy.

Sivars L, Landin D, Grün N, et al.
Validation of Human Papillomavirus as a Favourable Prognostic Marker and Analysis of CD8(+) Tumour-infiltrating Lymphocytes and Other Biomarkers in Cancer of Unknown Primary in the Head and Neck Region.
Anticancer Res. 2017; 37(2):665-673 [PubMed] Related Publications
BACKGROUND: Human papillomavirus (HPV) is a favourable prognostic factor in oropharyngeal cancer. Moreover, we and others reported that HPV-positive cancer of unknown primary in the head and neck region (HNCUP) has better outcome than HPV-negative HNCUP. However, not all studies concord. Here, our previous finding was investigated in a new cohort and additional biomarkers were analyzed.
MATERIALS AND METHODS: A total of 19 HNCUPs diagnosed 2008-2013 were analyzed for HPV DNA by polymerase chain reaction assay (PCR) and p16 by immunohistochemistry (IHC). Thereafter, 69 HNCUPs diagnosed between 2000-2013 were analyzed for HPV16 mRNA by PCR (if HPV16DNA-positive) and cluster of differentiation 8 positive (CD8(+)) tumour-infiltrating lymphocytes (TILs) and human leukocyte antigen (HLA) class I-expression using IHC.
RESULTS: HPV DNA, alone and in combination with p16 overexpression, was validated as a favourable prognostic factor in HNCUP. HPV16 mRNA was present in most HPV16 DNA-positive cases, confirming HPV-driven carcinogenesis in HNCUP. High CD8(+) TIL counts indicated favourable prognosis.
CONCLUSION: HPV status is useful for the management of patients with HNCUP and the role of CD8(+) TILs should be further explored.

Wichmann G, Cedra S, Schlegel D, et al.
Cilengitide and Cetuximab Reduce Cytokine Production and Colony Formation of Head and Neck Squamous Cell Carcinoma Cells Ex Vivo.
Anticancer Res. 2017; 37(2):521-527 [PubMed] Related Publications
BACKGROUND/AIM: To analyze ex vivo effects of combined targeting of the epidermal growth factor-receptor (EGFR) by cetuximab (E) plus αVβ3 and αVβ5 integrins by cilengitide (Cil) on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines in head and neck squamous cell carcinoma (HNSCC) cells.
MATERIALS AND METHODS: Collagenase-IV digests of 43 histopathological confirmed HNSCC cases were seeded into laminin-coated 96-well plates containing E, Cil, or Cil+E in final concentrations of 66.7 μg/ml, 10 μM, and 10 μM+66.7 μg/ml, respectively. Following the FLAVINO-assay protocol, supernatants were harvested after 3 days and adherent cells fixed in ethanol. Counting of CFec was facilitated by FITC-labeled pan-cytokeratin antibodies. Out of 43 HNSCC cases, 39 had adherent growth (mean CFec≥4/well in triplicate controls). Cytokines in supernatants were measured using ELISA were interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and vascular endothelial growth factor A (VEGFA).
RESULTS: CFec on laminin was significantly reduced by Cil, E, and Cil+E. Cytokine measurements also revealed significant suppression of MCP-1, IL-6 and VEGFA. The strongest suppression of CFec, MCP-1 and VEGFA release was exerted by Cil and E combined. Efficacy of Cil+E exceeded those of the solely applied pharmaceutics but failed regarding significant synergism of both treatments as E was unable to significantly boost the effects of Cil. In contrast, IL-6 release was significantly suppressed by E but not by Cil, while their combination strongly reduced it.
CONCLUSION: Combined targeting of EGFR and integrins with E and Cil heightens their suppressive effects regarding CFec as well as release of pro-angiogenetic and pro-inflammatory cytokines.

Boppana NB, Kraveka JM, Rahmaniyan M, et al.
Fumonisin B1 Inhibits Endoplasmic Reticulum Stress Associated-apoptosis After FoscanPDT Combined with C6-Pyridinium Ceramide or Fenretinide.
Anticancer Res. 2017; 37(2):455-463 [PubMed] Related Publications
BACKGROUND/AIM: Combining an anticancer agent fenretinide (HPR) or C6-pyridinium ceramide (LCL29) with Foscan-mediated photodynamic therapy (FoscanPDT) is expected to augment anticancer benefits of each substance. We showed that treatment with FoscanPDT+HPR enhanced accumulation of C16-dihydroceramide, and that fumonisin B1 (FB), an inhibitor of ceramide synthase, counteracted caspase-3 activation and colony-forming ability of head and neck squamous cell carcinoma (HNSCC) cells. Because cancer cells appear to be more susceptible to increased levels of the endoplasmic reticulum (ER) stress than normal cells, herein we tested the hypothesis that FoscanPDT combined with HPR or LCL29 induces FB-sensitive ER stress-associated apoptosis that affects cell survival.
MATERIALS AND METHODS: Using an HNSCC cell line, we determined: cell survival by clonogenic assay, caspase-3 activity by spectrofluorometry, the expression of the ER markers BiP and CHOP by quantitative real-time polymerase chain reaction and western immunoblotting, and sphingolipid levels by mass spectrometry.
RESULTS: Similar to HPR+FoscanPDT, LCL29+FoscanPDT induced enhanced loss of clonogenicity and caspase-3 activation, that were both inhibited by FB. Our additional pharmacological evidence showed that the enhanced loss of clonogenicity after the combined treatments was singlet oxygen-, ER stress- and apoptosis-dependent. The combined treatments induced enhanced, FB-sensitive, up-regulation of BiP and CHOP, as well as enhanced accumulation of sphingolipids.
CONCLUSION: Our data suggest that enhanced clonogenic cell killing after the combined treatments is dependent on oxidative- and ER-stress, apoptosis, and FB-sensitive sphingolipid production, and should help develop more effective mechanism-based therapeutic strategies.

Vrana D, Matzenauer M, Aujesky R, et al.
Potential Predictive Role of MicroRNAs in the Neoadjuvant Treatment of Esophageal Cancer.
Anticancer Res. 2017; 37(2):403-412 [PubMed] Related Publications
Esophageal cancer is a disease with disappointing prognosis. Currently, there are no predictive factors that can identify patients who on the one hand would likely benefit from tri-modality management and, on the other hand, would not be significantly affected by the morbidity accompanying the treatment. MicroRNAs are short non-coding RNAs responsible for post-transcriptional modification of gene expression by binding to 3'-UTR of messenger RNA and represent emerging potential predictive biomarkers of treatment (chemotherapy and radiotherapy) efficacy and toxicity. We reviewed the current literature, addressing the potential predictive role of microRNAs for efficacy of chemotherapy (specifically cisplatin, 5-fluorouracil, doxorubicin and paclitaxel) and radiotherapy, including predicted targets in the cell. Altogether 82 articles were identified and included in this review. This may be the first review on this topic specifically focusing on neoadjuvant treatment of esophageal cancer.

Li T, Sheng L, Chunyan C, et al.
The significance of diffusion tensor magnetic resonance imaging for patients with nasopharyngeal carcinoma and trigeminal nerve invasion.
Medicine (Baltimore). 2017; 96(6):e6072 [PubMed] Free Access to Full Article Related Publications
To investigate the significance of diffusion tensor imaging (DTI) for patients with nasopharyngeal carcinoma (NPC) and trigeminal nerve invasion.Fifty-two patients with NPC and unilateral infringement and 30 healthy controls were recruited for our study. Routine magnetic resonance imaging (MRI) and DTI were performed for all participants. Within-group and between-group comparisons of DTI metrics, including fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) of the third (V3) branch of the bilateral trigeminal nerves of all participants, were carried out.The FA and ADC values on the affected sides of patients revealed a significant decrease and increase, respectively, when compared with those on the unaffected sides of patients and the healthy controls (P = 0.000 for all), whereas there were no significant differences in DTI metrics between both sides of healthy controls or between the unaffected sides of patients and the healthy controls (P = 0.930, 0.580, 0.095, and 0.360, respectively). The decreasing FA rate on the affected sides of patients correlated negatively with the increasing ADC rate (r = -0.675, P = 0.000).DTI can quantitatively evaluate microstructural abnormalities of the V3 branch of the trigeminal nerve in patients with NPC, which is important for the early detection of trigeminal nerve invasion to achieve a precise T classification, assess prognosis, and guide treatment.

Hung TM, Fan KH, Chen EY, et al.
An elective radiation dose of 46 Gy is feasible in nasopharyngeal carcinoma treated by intensity-modulated radiotherapy: A long-term follow-up result.
Medicine (Baltimore). 2017; 96(6):e6036 [PubMed] Free Access to Full Article Related Publications
The purpose of this study is to compare the treatment outcome of different radiation doses of elective neck irradiation (ENI) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT).In total, 504 patients with nondisseminated NPC who underwent magnetic resonance imaging before radical IMRT between 2000 and 2008 were retrospectively reviewed. The patients were classified into 2 groups based on the ENI dose: low ENI when the ENI dose was 46 Gy (n = 446) and high ENI when the ENI doses were 50 to 60 Gy (n = 58). All the patients in both the groups received a median dose of 72 Gy to the gross tumor and involved nodes. The fraction size was 2 Gy per fraction. Matching was performed between low ENI and high ENI in a 2:1 ratio, and the matching criteria were N-stage, T-stage, treatment modality, pathology classification, sex, and age.The median follow-up for all patients was 63.5 months. In all patients, the 5-year progression-free survival (PFS), local control (LC), regional control (RC), distant metastasis-free survival (DMFS), overall survival (OS), and cancer-specific survival (CSS) for low ENI and high ENI patients were 69.0% and 63.2% (P = 0.331), 89.0% and 83.9% (P = 0.235), 90.1% and 85.2% (P = 0.246), 86.8% and 76.6% (P = 0.056), 77.5% and 80.8% (P = 0.926), and 84.4% and 82.5% (P = 0.237), respectively. In the matched-pair analysis, the 5-year PFS, LC, RC, DMFS, OS, and CSS for matched low ENI and high ENI patients were 74.1% and 63.2% (P = 0.134), 92.0% and 83.9% (P = 0.152), 90.1% and 85.2% (P = 0.356), 86.2% and 76.6% (P = 0.125), 87.0% and 80.8% (P = 0.102), and 88.6% and 82.5% (P = 0.080), respectively. In the multivariable analysis for all patients, the ENI group was not a significant factor for PFS, LC, RC, DMFS, OS, and CSS.A low ENI dose of 46 Gy in 23 fractions is feasible in NPC patients treated with IMRT, and this concept should be validated in the prospective studies.

Najafian A, Kahan S, Zeiger MA, Olson MT
Unusual findings in thyroid cytology and histology.
Diagn Cytopathol. 2017; 45(3):185-190 [PubMed] Related Publications
INTRODUCTION: Although cytology and histopathology of thyroid lesions generally fall into common, well-defined categories, there are uncommon cases with unusual fine needle aspiration (FNA) findings or histology. Herein, we review the prevalence and characteristics of rare thyroid cytology and histopathology findings at a tertiary hospital.
METHODS: Institutional data from >31,000 patients with a thyroid pathology from 1995 to 2013 were queried. Both cytology and histology were available in 6,693 patients. After exclusion of the common cytological categories detailed by The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and common histopathology categories, 90 patients with either an unusual FNA, histopathology, or both were identified.
RESULTS: A total of 90 cases were included (19: only unusual FNA; 25: only unusual histology; 46: both unusual cytology and histopathology). The positive predictive value of an unusual FNA for discovering an unusual lesion was 71% (95% CI: 58%-81%). The majority (66%) were females and median age was 59 years. On histopathology, 80 (88%) cases were malignant, 72 (90%) of which were initially diagnosed as malignant on FNA. Of the 10 benign lesions, 8 (80%) also had a benign FNA. Patients with unusual malignant lesions were significantly older than those with unusual benign lesions (62 vs. 44 years; P: 0.004).
CONCLUSION: Unusual cytopathological and histopathological findings in thyroid comprise a varied group of tumors that are individually rare but collectively common. A preoperative FNA with an unusual cytopathology is likely to lead to an unusual histopathological diagnosis; however, its diagnostic accuracy in differentiating benign from malignant is lower than the accuracy of cytopathology of conventional TBSRTC. Diagn. Cytopathol. 2017;45:185-190. © 2016 Wiley Periodicals, Inc.

Ishihara R, Matsuura N, Hanaoka N, et al.
Endoscopic imaging modalities for diagnosing invasion depth of superficial esophageal squamous cell carcinoma: a systematic review and meta-analysis.
BMC Gastroenterol. 2017; 17(1):24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diagnosis of cancer invasion depth is crucial for selecting the optimal treatment strategy in patients with gastrointestinal cancers. We conducted a meta-analysis to determine the utilities of different endoscopic modalities for diagnosing invasion depth of esophageal squamous cell carcinoma (SCC).
METHODS: We conducted a comprehensive search of MEDLINE, Cochrane Central, and Ichushi databases to identify studies evaluating the use of endoscopic modalities for diagnosing invasion depth of superficial esophageal SCC. We excluded case reports, review articles, and studies in which the total number of patients or lesions was <10.
RESULTS: Fourteen studies fulfilled our criteria. Summary receiver operating characteristic curves showed that magnified endoscopy (ME) and endoscopic ultrasonography (EUS) performed better than non-ME. ME was associated with high sensitivity and a very low (0.08) negative likelihood ratio (NLR), while EUS had high specificity and a very high (17.6) positive likelihood ratio (PLR) for the diagnosis of epithelial or lamina propria cancers. NLR <0.1 provided strong evidence to rule out disease, and PLR >10 provided strong evidence of a positive diagnosis.
CONCLUSIONS: EUS and ME perform better than non-ME for diagnosing invasion depth in SCC. ME has a low NLR and is a reliable modality for confirming deep invasion of cancer, while EUS has a high PLR and can reliably confirm that the cancer is limited to the surface. Effective use of these two modalities should be considered in patients with SCC.
TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews); number 42015024462 .

Kim J, Cho SG, Kang SR, et al.
Preparation for radioactive iodine therapy is not a risk factor for the development of hyponatremia in thyroid cancer patients.
Medicine (Baltimore). 2017; 96(5):e6004 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to evaluate whether the preparation for radioactive iodine (RAI) therapy by thyroid hormone withdrawal (THW) or a low-iodine diet (LID) can be risk factors for the development of hyponatremia in patients with differentiated thyroid cancer after thyroidectomy.We retrospectively reviewed the medical records and laboratory findings of 326 patients who underwent preparation for RAI therapy after thyroidectomy from 2012 to 2014. Demographic and clinical variables including the method of thyrotropin stimulation and duration of LID were assessed. Serum sodium was measured twice, before operation and before RAI therapy.Hyponatremia was detected in only 3 patients (0.9%) before operation, but in 15 patients (4.6%) before RAI therapy. None of the patients had severe hyponatremia after preparation for RAI therapy. Pre-RAI therapy serum sodium was correlated with the method of thyrotropin stimulation (TWH vs recombinant human thyroid stimulating hormone, P = 0.014) and duration of LID (r = -0.131, P = 0.018); however, the preparation of RAI therapy, THW and LID, did not affect the development of hyponatremia in logistic regression analysis. Preoperative serum sodium was a significant risk factor for hyponatremia during preparation for RAI therapy.Preparation for RAI therapy by THW or LID is not a risk factor for the development of hyponatremia in patients with thyroid cancer. The development of hyponatremia was neither frequent nor severe during preparation for RAI therapy. Physicians should not be greatly concerned about rare life-threatening hyponatremia during preparation for RAI therapy.

Ouyang DQ, Liang LZ, Zheng GS, et al.
Risk factors and prognosis for salivary gland adenoid cystic carcinoma in southern china: A 25-year retrospective study.
Medicine (Baltimore). 2017; 96(5):e5964 [PubMed] Free Access to Full Article Related Publications
Adenoid cystic carcinoma (ACC) is characterized by slow growth, frequent local recurrences, and high incidence of distant metastasis (DM). The aim of this study was to evaluate predictive factors for local-regional (LR) recurrence, DM, and survival in ACC.A retrospective review of the medical records for patients with salivary glands ACC from 1990 to 2015 was performed. The clinical parameters were assessed to identify correlations with the development of LR recurrence, DM, and survival of these patients.Among 228 patients who underwent surgery as definitive treatment, 210 (92.1%) were followed up in the study. DM was detected in 64 (30.5%) patients, LR recurrence was detected in 58 (27.6%) patients. The estimated 5, 10, and 15-year overall survival rates were 84.7%, 70.8%, and 34.0%, respectively. Multivariate analysis revealed that the presence of lymphovascular invasion and a high T classification were very strong adverse factors, which independently influenced LR recurrence, DM, and survival of ACC patients. Positive/close margin and N+ status were independent risk factors for DM and LR recurrence, respectively. Survival of ACC patents was also affected by tumor location.Presence of lymphovascular invasion and a high T classification were very strong adverse factors and independent predictors for ACC patients' prognosis, which influenced LR control, DM control, and survival.

Lin X, Khalid S, Qureshi MZ, et al.
VEGF mediated signaling in oral cancer.
Cell Mol Biol (Noisy-le-grand). 2016; 62(14):64-68 [PubMed] Related Publications
Increasingly it is being realized that oral cancer arises from genetic/epigenetic mutations, dysregulations of spatio-temporally controlled signal transduction cascades and loss of apoptosis. Epidemiological studies have provided a stronger association between tobacco use (chewed and smoked) and oral cancer. Nevertheless, alcohol has also gained attention as a significant risk factor, having a multiplicative synergistic cancer promoting effect with tobacco. Vascular Endothelial Growth Factor (VEGF) mediated signaling has gained limelight because of its instrumental role in endothelial cell proliferation, survival, invasion, migration, chemotaxis of bone marrow (BM)-derived progenitor cells, vasodilation and vascular permeability. In this review we provide most recent updates on involvement of VEGF/VEGFR signaling axis in oral cancer. We partition this multi-component review into different sections and summarize latest advancements related to therapies against VEGF/VEGFR signaling axis and how microRNAs tactfully modulate VEGF and VEGFR in oral cancers. Data obtained through preclinical and clinical studies has revealed that therapeutic benefits associated with VEGF-targeted therapy are complicated in different cancers and involve myriad of mechanisms. A better understanding of VEGF/VEGFR mediated signaling in oral cancers and testing of novel therapeutic agents in preclinical models will prove to be helpful in effective translation of safest drugs from benchtop to the bedside.

Vishwakarma S, Agarwal R, Goel SK, et al.
Altered Expression of Sphingosine-1-Phosphate Metabolizing Enzymes in Oral Cancer Correlate With Clinicopathological Attributes.
Cancer Invest. 2017; 35(2):139-141 [PubMed] Related Publications
We have determined the gene expression of sphingosine-1-phosphate (S1P) metabolizing enzymes (SphK1, SphK2, SGPL1, SGPP1, SGPP2, PPAP2A, PPAP2B, and PPAP2C) by quantitative real-time polymerase chain reaction in tumor tissues and adjacent normal tissues of 50 oral squamous cell carcinoma (OSCC) patients. Expression of SphK1 and SGPP1 genes was up-regulated significantly in 70% and 75% OSCC tumors respectively. Importantly, expression of SphK2 and PPAP2B was down-regulated in the tumor tissues of 70% OSCC patients. Expression of SphK2 and PPAP2B negatively correlated with tumor-node-metastasis (TNM) staging and tumor volume respectively. Furthermore, LPP1 is an independent predictor of TNM staging and lymph node ratio.

Hsieh R, Nico MM, Camillo CM, et al.
Mutational Status of NRAS and BRAF Genes and Protein Expression Analysis in a Series of Primary Oral Mucosal Melanoma.
Am J Dermatopathol. 2017; 39(2):104-110 [PubMed] Related Publications
Primary oral mucosal melanoma is an extremely rare and aggressive tumor arising from melanocytes located in the mucosal epithelium of the oral cavity. Although malignant melanoma of oral mucosa shares some clinical features with its cutaneous counterpart, it has been associated with a worst prognosis; its etiopathogenesis are still only partially unraveled as there is no influence of UV radiation. It is known that the mitogen-activated protein kinase pathway mediates cellular responses to growth signals and its activation is an important phenomenon in melanoma. The aim of this study was to evaluate NRAS and BRAF genes, both components of mitogen-activated protein kinase molecular pathway, and compare with their protein expression. Point mutations of NRAS (codons 12, 13, and 61) and BRAF (codon 600) were screened by pyrosequencing method, and its results were associated to the protein expression of RAS and BRAF performed by immunohistochemistry. The authors observed mutation in BRAF 600 (3/14), NRAS codons 12 and 13 (2/14), and NRAS codon 61 (2/8). One case showed positive RAS protein expression, but no mutation was observed. Twelve in 14 cases showed positive BRAF protein expression: 3 cases showed BRAF mutation; 2 cases showed NRAS codon 61 mutation; 2 cases showed NRAS codons 12 and 13 mutation but not simultaneously. Although NRAS and BRAF mutation frequency and RAS protein expression are low, BRAF protein expression was intense; probably, NRAS and BRAF mutations are independent events and alternative molecular mechanisms in the primary oral mucosal melanoma tumorigenesis.

Bernadt CT, Collins BT
Fine-needle aspiration biopsy of HPV-related squamous cell carcinoma of the head and neck: Current ancillary testing methods for determining HPV status.
Diagn Cytopathol. 2017; 45(3):221-229 [PubMed] Related Publications
Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is a unique form of carcinoma that largely arises from the tonsillar tissue in the oropharynx. These tumors often present with cervical lymphadenopathy resulting in a fine needle aspiration (FNA) biopsy. Use of the cytology specimen to determine the HPV-status has significant prognostic and treatment implications as HPV-related tumors have a more favorable prognosis and response to nonsurgical therapies. While several different ancillary testing methods are available that have proven effective for determining HPV status in FNA specimens from HNSCCs, there is currently no consensus regarding HPV testing in this setting. Diagn. Cytopathol. 2017;45:221-229. © 2016 Wiley Periodicals, Inc.

Feng JF, Chen S, Yang X
Systemic immune-inflammation index (SII) is a useful prognostic indicator for patients with squamous cell carcinoma of the esophagus.
Medicine (Baltimore). 2017; 96(4):e5886 [PubMed] Free Access to Full Article Related Publications
The aim of the study was to determine the prognostic role of systemic immune-inflammation index (SII) in patients with esophageal squamous cell carcinoma (ESCC).A total of 298 ESCC patients were enrolled in the current retrospective study. The SII was calculated by the formula: neutrophil × platelet/lymphocyte. The optimal cut-off value was calculated by the Cutoff Finder. Univariate and multivariate analyses were evaluated for cancer-specific survival (CSS). Additional, we also established a nomogram model to predict the prognosis for patients with ESCC.The optimal cut-off value was 410 × 10/L for SII. Patients with SII ≤ 410 (×10/L) had a significantly better 5-year CSS than patients with SII > 410 (×10/L) (51.9% vs 24.0%, P < 0.001). Multivariate analyses revealed that SII was a significant independent predictive indicator (P = 0.027). A nomogram could be more accuracy for CSS for patients with ESCC (c-index: 0.68).The SII is a useful independent prognostic indicator for patients with resectable ESCC.

Noda Y, Kishino M, Sato S, et al.
Galectin-1 expression is associated with tumour immunity and prognosis in gingival squamous cell carcinoma.
J Clin Pathol. 2017; 70(2):126-133 [PubMed] Related Publications
AIMS: Galectin-1 (Gal-1) is a β-galactoside-binding protein that overexpresses in cancer and plays pivotal roles in tumour progression. Gal-1 regulates angiogenesis and invasiveness, and suppresses tumour immunity by inducing T cell apoptosis. Several studies have examined the relationship between Gal-1 and tumour immunosuppression in vivo, but they have not examined the clinicopathological relationship between Gal-1 expression and apoptotic T cell number in human tissue. In this study, we investigated the association between Gal-1 expression and apoptotic T cells of gingival squamous cell carcinoma (GSCC), as well as other clinicopathological factors.
METHODS: Immunohistochemical investigation of 80 GSCC specimens using anti-Gal-1, anti-CD3, anti-CD4, anti-CD8, anti-CD34, antipodoplanin and anticleaved caspase-3 (CC-3) antibodies was performed. Relative expression levels of CD3 and CC-3, as well as CD8 and CC-3 were assessed simultaneously by double immunostaining. Gal-1 expression and T cell apoptosis were evaluated in 6 high-power fields (3 in the tumour and 3 in the stroma).
RESULTS: Gal-1 expression in GSCC was significantly correlated with T cell infiltration (p=0.036), and apoptosis of CD3+ and CD8+ T cells (p<0.001). Moreover, Gal-1 expression was significantly correlated with lymph node metastasis (p=0.021), histological differentiation (p<0.001) and overall survival rate (p=0.021).
CONCLUSIONS: These findings suggest that Gal-1 plays an important role in immune escape of GSCC cells, and Gal-1 expression level may be a useful clinicopathological prognostic marker for GSCC.

Mínguez P, Flux G, Genollá J, et al.
Whole-remnant and maximum-voxel SPECT/CT dosimetry in (131) I-NaI treatments of differentiated thyroid cancer.
Med Phys. 2016; 43(10):5279-5287 [PubMed] Related Publications
PURPOSE: To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC).
METHODS: Eighteen DTC patients were administered 1.11 GBq of (131) I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3-7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimated using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry.
RESULTS: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in theS-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients.
CONCLUSIONS: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.

Sera T, Kashiwagi S, Takashima T, et al.
Multiple metastatic malignant phyllodes tumor of the breast with tonsillar metastasis: a case report.
BMC Res Notes. 2017; 10(1):55 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tonsillar metastasis is very rare and accounts for only 0.8% of tonsillar tumors. And phyllodes tumor of the breast with tonsillar metastasis is very rare.
CASE PRESENTATION: A 57-year-old Japanese woman received surgery (partial mastectomy) of malignant phyllodes tumor. Seven months after initial surgery, pharyngeal pain, swelling, and a feeling of dyspnea developed, and tumor was found in the left palatine tonsil. Computed tomography for further evaluation showed a tonsillar lesion with contrast enhancement, and tonsillar metastasis was suspected. The metastatic lung tumors had not progressed. Laryngoscopic biopsy showed a tonsillar metastasis from the malignant phyllodes tumor. Despite the diagnosis of malignant phyllodes tumor with tonsillar and pulmonary metastases, the patient refused further treatment and died about 1 month later.
CONCLUSIONS: A patient with a malignant phyllodes tumor of the breast and tonsillar metastasis was reported, along with a discussion of the relevant literature of this very rare pattern of metastasis.

Liu Y, Li H, Zhang J, Gao X
Potassium Iodate Differently Regulates the Proliferation, Migration, and Invasion of Human Thyroid Cancer Cells via Modulating miR-146a.
Cancer Invest. 2017; 35(2):122-128 [PubMed] Related Publications
The effects of different doses of potassium iodate (KIO3) on the malignancy of thyroid cancer were investigated. Results showed that the proliferation, migration, and invasion of SW579 thyroid cancer cells were improved by 10(-6) M KIO3, which was associated with microRNA(miR)-146a deficit; 10(-2) M KIO3 significantly enhanced miR-146a level and suppressed SW579 cell proliferation, migration, and invasion. The diverse effects of KIO3 on SW579 cells were associated with the expression changes in miR-146a targets, Bcl-2, Bax, and caspase-3. Our study concludes that different doses of KIO3 have counteracting effects on the malignancy of thyroid cancer through modulating miR-146a level.

Grozinsky-Glasberg S, Bloom AI, Lev-Cohain N, et al.
The role of hepatic trans-arterial chemoembolization in metastatic medullary thyroid carcinoma: a specialist center experience and review of the literature.
Eur J Endocrinol. 2017; 176(4):461-468 [PubMed] Related Publications
BACKGROUND: Liver metastases are relatively common in patients with metastatic medullary thyroid carcinoma (MTC), carrying a negative impact on disease prognosis. The options for selective therapy of liver metastases in MTC patients are limited to catheter-guided procedures such as trans-arterial chemoembolization (TACE). Data regarding the effectiveness and safety of this procedure in MTC are limited.
AIM: To explore the clinical outcome, survival and safety profile of TACE for liver metastases in a group of MTC patients.
METHODS: Retrospective case series of patients treated at a single tertiary University Medical Center from 2005 to 2015.
RESULTS: Seven consecutive patients (mean age 64.5 ± 10.9 years, 5 females) with histologically confirmed MTC with liver metastases were included. Metastatic involvement of the liver was less than 50% of the liver volume in all patients. The median size of the largest liver lesion was 40 ± 6.9 mm. The patients underwent in total 20 sessions of TACE. Clinical improvement as well as tumor response (PR) were observed in all patients. The median time to tumor progression was 38 months (range 8-126). Three patients were still alive at the end of the follow-up period (a median overall survival rate of 57 ± 44 months).
CONCLUSION: TACE in MTC patients with hepatic metastases is usually well tolerated and induces both clinical improvement and tumor response for prolonged periods of time in the majority of patients. This therapeutic option should always be considered, irrespective of the presence of extrahepatic metastasis.

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